Adenosine triphosphate citrate lyase: Emerging target in the treatment of dyslipidemia

- LDL-C goal attainment remains low, partly due to scarcity of alternatives to statins.
- ACL is the cytosolic enzyme that provides acetyl coenzyme A for lipid synthesis.
- Inhibition of ACL reduces cellular lipid synthesis in vitro and in vivo.
- ETC-1002 is an oral ACL inhibitor for once-daily administration.
- ETC-1002 has shown encouraging efficacy and safety on LDL-C in phase I and II clinical studies.

Despite major advances in pharmacologic therapy over the last few decades, dyslipidemia remains a prevalent, insufficiently recognized, and undercontrolled risk factor for cardiovascular disease. Statins are the mainstay of hypercholesterolemia treatment, but because of adherence and tolerability issues that limit dose titration, there is a need for additional therapies with good efficacy and better tolerability. Adenosine triphosphate (ATP) citrate lyase, a cytoplasmic enzyme responsible for the generation of acetyl coenzyme A for the de novo synthesis of fatty acids and cholesterol, is a very interesting molecular target for the reduction of plasma lipids. Furthermore, ATP citrate lyase inhibition may be accompanied by activation of 5′-adenosine monophosphate-activated protein kinase, a key signaling molecule that acts a central hub in cellular metabolic regulation. ETC-1002 is a small molecule inhibitor of ATP citrate lyase that also activates 5′-adenosine monophosphate-activated protein kinase, effectively reducing low-density lipoprotein cholesterol and inducing some other positive metabolic changes. Recent evidence from phase I and II clinical trials in humans has shown a positive efficacy and safety profile of ETC-1002, with low-density lipoprotein cholesterol reductions similar to those attainable by usual doses of many statins and with no major apparent side effects. These results potentially introduce a new family of medications that may expand our therapeutic arsenal against hypercholesterolemia.